Design And Synthesis Of Chiral N,O-Ligands And Their Applications In Asymmetric Addition Reactions

Chirality is the universal characteristic of the nature. Many chiral compounds have a lot of good physical activities and pharmacological activities. In 2001, the Nobel Prize was awarded to the three outstanding chemists, William S. Knowles, Ryoji Noyori and Sharpless who made outstanding contributions to their research in the field of the asymmetric catalysis. Their research greatly advanced the development of pharmaceutical companies and stimulated the chemists of all the world with great interest in this area. From that time on, asymmetric synthesis has become a very active area. Asymmetric catalytic reaction is an extremely important area of the field of which the significance and value is self-evident.As we known, the reaction catalyzed by metal catalyst is still the most important way to obtain optical pure compounds in the field of asymmetric catalytic reactions. Design and synthesis of new chiral ligands is one of the most attracting area. Suitable structure of the chiral ligand is the key to achieve high enantioselectivities in the asymmetric catalytic reactions. In this paper, our reasearch focus on the design and synthesis of the novel chiral N,O ligands and their applications on the asymmetric addition reactions. This thesis is divided into three parts.1. In the first part, there are three charpters and reports the studies on the asymmetric transfer hydrogenation reaction of ketones in water and the ATH reaction of the amino ketones. As we known from the literatures, there are few chiral ligands that suitable to catalyze the ATH reaction in water. Furthermore, there are few papers reported the ATH reaction of new substrates using excellent catalysts. In this case, it is necessary to develop some new chiral ligands to catalyze the ATH reaction in water and to broaden the applications of those excellent catalysts. The reasearch on the realationships between the ligands structures and the product configuration is still limitless. We focus on this area and get some satisfied results as followings:(1) The readily available amino alcohol (1R,2S)-cis-1-aminoindan-2-ol was employed into the [RuCl2(p-cymene)]2-catalyzed asymmetric transfer hydrogenation of prochiral ketones performed on crude water. The reaction was performed in the open-vessel at room temperature with moderate to good conversions and enantioselectivities. N-substitution of (1R,2S)-cis-1-aminoindan-2-ol could lead to the reversal of the configuration of the product under the same condition in the same catalytic reaction. A reasonable mechansim was proposed.(2) A number of optically active amino alcohols were synthesized via ATH reaction of the corresponding amino ketones directly with good to high ees and excellent yields. When the substrates were broaden toβ-sulfonamido ketones andβ-keto sulfone, 100% ee of the products were obtained. The important chrial building blocks, aziridines was also obtained via a Mitsunbo reaction of the amino alcohol. The absolute configuration of the amino alcohols was confirmed to be R by X-ray analysis.2. During the second part, three kinds of N,O ligands were reported to catalyzed the addition reaction of phenylacetylene to aldehydes. Chiral propargyl alcohols are versatile building blocks for asymmetric synthesis. There are two main methods to obtain the important compouds. One is the asymmetric reduction of the acetylenic ketones. Another is the enantioselective alkyne addition to aldehydes. Obviously, the latter method has more advantages than the former. Most of the chiral ligands using in this reaction are amino alcohols based on ephedrine or binapthyl-derived. Thus, it is necessary to develop the other kinds of chiral ligands in order to promote the development of the asymmetric catalytic reaction.(1) The readily available and inexpensive new chiral oxazolidine in combination with Ti(OiPr)4 was found to catalyze the reaction of an alkynylzinc reagent with various types of aldehydes to generate chiral propargylic alcohols with high enantioselectivities (up to 95%) and excellent yields (up to 98%). This was the first example of chiral ligand-Ti-Zn catalytic system to catalyze the enantioselective alkyne addition to aldehydes.(2) Although some secondary or tertiary amino alcohols were reported as the chiral ligands for asymmetric alkynylation of aldehydes, little attention was paid on the use of primary amino alcohols to catalyze the asymmetric addition of terminal alkynes to aldehydes. We reported the first sucessfully unmodified available chiral amino alcohol (1S,2S)-2-amino-1,2-diphenylethanol in combination with Ti(OiPr)4 to catalyze the reaction of an alkynylzinc reagent with various aldehydes to generate chiral propargylic alcohols with moderate to good yields and enantioselectivities. When chiral primary amino ligand was used to catalyze the reaction, (S)-product with only 17% ee was obtained. Addition of Ti(OiPr)4 to the reaction lead to the enhanced ee of the prodct greatly with opposite absolute configuration.(3) The easily prepared chiral tertiary amino alcohol derived from L-proline was found to catalyze the reaction of alkynylzinc reagents with various aldehydes to generate chiral propargylic alcohols with moderate-to-good enantioselectivities (71–83% ee). The mechanism of the reaction was also discussed in the thesis. In order to explain the realationship between the ligand structure and the configuration and ee of product, a novel theoretical computation of those evaluated ligands was introduced which may supply valuable experience to help designing new chiral ligands.We have found that the suitable match between the ligands and center metal was very important for this asymmetric addition reaction. So what kinds of ligands coodinate with central metal zinc or titanium is a good catalytic system? Generally speaking, in order to get a good catalyst system, primary amino alcohols or sulfonyl amide alcohols or ammonia alcohols are better to coodinate with central metal titanium than zinc, while tertary amino alcohols are better to coodinate with central metal zinc than Ti. Secondary amino alcohol has dual characters. Sometimes, it may favour to coodinate with Zn, while in the other case, it may favour to coodinate with Ti. Furthermore, in order to find the inherent correlationship between ligand structure and product configuration, the electron cloud density of nitrogen atoms in the ligand was studied via theoretical calculations. This may supply helpful ideas to guide us to design new ligands.In the last part, the homocoupling reaction of phenylboronic acids catalyzed by Pd(OAc)2 was studied. Moderate to good yields of symmetrical biaryls (25–97%) were achieved under very mild conditions via homocoupling of arylboronic acids catalyzed by 3 mol% Pd(OAc)2 / 2.5 equiv. K2CO3 under air without using ligand in. acetone/water (v/v = 1:1) at room temperature. It provides a convient method to synthesize symmetrical biaryls.